DESCRIPTION: Autosomal dominant Alzheimer's disease (AD) has informed the field of AD research about the - Further, molecular and biochemical mechanisms that are believed to underlie the athological basis of AD mutations from autosomal dominant AD have provided animal and cellular models that are utilized to develop anti-A drugs. Prevention trials of autosomal dominant AD are likely to pioneer approaches for prevention - trials for all forms of AD. This proposal for a phase 3 pivotal cognitive endpoint trial of the leading amyloid- - beta modifying treatment from the ongoing phase 2 Dominantly Inherited Alzheimer's Network - Trial Unit (DIAN TU) biomarker trial aims to prevent cognitive loss in the autosomal-dominant AD population. Results - will advance the search for surrogate biomarkers and for a pathway to preventing AD in the general population. If this single phase 3 trial is positive, it may lead to te approval of a disease modifying drug for prevention. The DIAN-TU has founded the Collaboration for Alzheimer's Prevention (CAP) with the complementary-Alzheimer Prevention Initiative (API) and the ADCS Anti Amyloid treatment in Asymptomatic AD (A4) to ensure processes are efficient, public dollars are well spent, and results will advance the entire field. The DIAN TU established the DIAN Expanded Registry (www.DIANXR.org) and identified additional potential D-IAN-TU trial sites to enable the larger phase 3 prevention trial by increasing the number of participants to more than 3,000. The first prevention trial, a phase 2 biomarker trial, for people at risk of autosomal dominant AD was launched in December, 2012. The DIAN-TU Adaptive Prevention Trial (APT) leverages the existing infrastructure of the DIAN observational study and the DIAN-TU, and enrolls DIAN-TU participants as well as people at risk of autosomal dominant AD from associated sites. The DIANTU APT is the logical next step of the DIAN observational study. The patients are motivated, as this trial is the first concrete hope most have encountered after decades of research participation. The trial design is a randomized, double-blinded placebo controlled two arm trial of the selected best performing safety, tolerability and biomarker efficacy fibrillar anti-A antibody, a soluble anti-A antibody,or a beta-secretase inhibitor in 266 (n=133 per arm) asymptomatic autosomal dominant AD mutation carriers. Subjects will receive either drug or placebo for four years to determine clinica and cognitive benefit engagement of the CNS mechanism of action and downstream AD biomarkers. The drug arm will be compared to the placebo arm with the primary outcome of CDR Sum-of-Boxes and secondary outcomes of cognitive measures, computerized cognitive battery, safety, and AD biomarkers.